Preparation of powder agglomerates

ABSTRACT

The invention relates to a method of producing an agglomerate of drug and solid binder. The process involves producing individual agglomerate particles and then converting the convertible amorphous content of same, following agglomeration, by the application of, for example, moisture. Agglomerates capable of conversion as well as the finished agglomerates and oral and nasal dosing systems including same are also contemplated. The process produces agglomerates which are rugged but which will produce an acceptable fine particle fraction during dosing.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.11/028,788, filed on Jan. 4, 2005 which is a continuation of U.S. patentapplication Ser. No. 10/326,327, flied on Dec. 19, 2002 which is itselfa continuation of U.S. patent application Ser. No. 09/824,377 filed Apr.2, 2001, now issued as U.S. Pat. No. 6,503,537, granted Jan. 7, 2003,which is a continuation of U.S. patent application Ser. No. 09/042,973,filed Mar. 17, 1998, which claimed benefit of priority to U.S.Provisional Application Ser. No. 60/041,055, filed Mar. 20, 1997.Benefit of priority to all of said applications is hereby formallyclaimed.

FIELD OF THE INVENTION

The present invention relates broadly to the formation of agglomerates.More specifically, the present invention relates to the field ofpharmaceutical dosage form design and, in particular, the production ofunique agglomerated dosage forms for administration of pharmacologicallyactive agents to patients. The formulations in accordance with thisinvention are particularly well suited for oral and/or nasal inhalation.

INTRODUCTION TO THE INVENTION

There are several known methods of treating diseases and conditions ofthe upper and lower airway passages and the lungs. These conditionsinclude, for example, asthma and rhinitis. One such technique involvesadministering certain pharmacologically active agents or drugs such as,for example, mometasone furoate, topically to the airway passages orlungs in an immediately useable form. Mometasone furoate is a topicallyeffective, steroidal anti-inflammatory.

Oral inhalation therapy is one method of delivering such topicallyactive drugs. This form of drug delivery involves the oraladministration of a dry powdered drug directly to the afflicted area ina form which is readily available for immediate benefit.

However, inhalation therapy is a particularly demanding dosing systemand it involves its own set of unique design and performance problems,Amongst those problems is a concern over the accuracy and repeatabilityof dosing. One must try to ensure that the same amount of drug isadministered each and every time. Moreover, unlike pills, capsules andcreams, oral inhalation therapy must concern itself with not only thedosage form itself, but also a drug delivery device and the interactionbetween them. One has only to consider over-the-counter nasal sprays tounderstand this problem. When one squeezes a conventional squeezebottle, it is difficult to apply the same amount of force each and everytime. With even a slight difference in force, differences in the amountof drug administered can result. Even with somewhat more consistent pumpstyle spray applicators, variations in dosing can occur. While suchvariation is usually not a problem when administering OTC nasal sprays,variation should be minimized where possible when administeringprescription medications for such serious conditions as asthma. Thedangers of over-medicating or under-medicating and the consequences ofsuch unwanted deviation can be profound. The problem becomes even morecomplex when the size of the doses are as small as they often are inoral inhalation therapy.

To help mitigate these problems, companies such as Schering Corporationhave developed complex and highly accurate inhaler systems foradministering powdered medications such as those described in PCTInternational Publication No. WO 94/14492, which was published on Jul.7, 1994, the text of which is hereby incorporated by reference. Suchinhaler systems were designed to meter out an exact dose of a powderedmedication using a dosing hole of a specific size. The hole iscompletely filled with drug prior to administration and the entirecontents of the dosing hole are then delivered to the patient through anozzle. The dosing hole is then filled again for the next dose. Thesedevices have been specifically designed to remove, as much as possible,human error and mechanically induced variability in dosing.

While such devices represent a significant advance in oral inhalationtherapy, there are still some circumstances in which problems mayremain. These problems often center on the properties of thepharmacologically active agent and their interaction with the inhaler,For example, certain drugs are not “free-flowing” and that may make itdifficult to move the drug from storage in a reservoir, to measurementin a dosing hole, to delivery, from the inhaler. Other drugs may sufferfrom electrostatic charge problems or may exhibit an unacceptable degreeof cohesive force. Such drugs may be “sticky,” even when in powderedform. These drugs may clog the inhaler/applicator, affecting its abilityto properly meter the intended amount of medication. Such powders mayalso adhere to the nozzle of the applicator, thus reducing the amount ofmedication actually delivered. This is often referred to as “hang up.”Drugs may also be “fluffy” which makes handling and loading sufficientdrug into a dosing hole a real challenge. To make matters even worse,these and other physical properties of various pharmacologically activeagents may vary within a single batch of material. This can defeatattempts to compensate.

Related problems may also result based upon the small size of theparticles which are generally used in inhalation therapy. Inhalationtherapy commonly involves drug particles which are on the order of 10 μmor below. This ensures adequate penetration of the medicament into thelungs of the patient as well as good topical coverage. In order toprovide adequate dispensing of such medicines, tight control must bemaintained on the size of the particles of the drug. However, powders ofthis size can be extremely difficult to work with, particularly whensmall dosages are required. Such powders are typically not free-flowingand are usually light, dusty or fluffy in character, creating problemsduring handling, processing, and storing. In addition, it can bedifficult to repeatedly and accurately load such materials into thedosing hole of an inhaler. Thus not only the properties of the drug, butalso the required size of the therapeutic particulate, can combine tocause considerable problems in terms of handling and dosing.

One method of improving the ability to administer fine powderedmedicaments is by the inclusion of dr excipients such as, for example,dr lactose. However, it has been determined that when particularly smalldoses of medication are required, such as under about 100-200 μg ofdrug, the inclusion of conventional excipients may not adequatelycompensate for the problems associated with the use of fine drugparticles. In addition, dry excipients as commonly used, generally haveparticle sizes which are significantly larger than the particle size ofthe drug. Unfortunately, the use of such large particles can have asignificant impact on the amount of drug delivered from dose to dose.Moreover, the intended benefits of the use of such excipients begins todiminish as the size of the dose decreases. Therefore, drug hang up orretention within the metering device or the inhalation nozzle and otherhandling issues can become an increasing problem.

Alternatively, drug products can be processed to form agglomerates orpellets which are generally more free-flowing and bulky. One method ofagglomerating drugs is described in PCT International Publication No. WO95/09616, published on Apr. 13, 1995. As described therein, agglomeratesof finely divided powder medicaments, such as micronized powders havinga particle size smaller than 10 μm, can be produced which require nobinders. However, they can be formed with excipients. These agglomeratescan then be administered through an inhaler for powdered medications.

The ability to create particles without a binder is significant toinhalation therapy and can pose a great advantage over other techniqueswhich use water or other traditional binders in agglomerate formation.Agglomerates of pure drug can provide great advantages when formulatingand handling powders. It has been found, however, that at doses of about100-200 μg, of a drug such as mometasone furoate, and below,agglomerates of pure drug can suffer from hang up and dosing variabilitycan be a genuine concern. Even in dosing systems designed to providerelatively larger doses of pharmacologically active agent, such as about400 μg or above, the resulting agglomerates of pure drug can stillsuffer from integrity problems. These agglomerates are still relativelysoft and can be crushed during metering thereby providing variability indosing. The material can also be broken fairly readily by, for example,dropping an inhaler from a height of about four feet. This wouldprematurely result in the formation of smaller particles which are moredifficult to handle. In fact, it is the handling difficulties of thefine drug particles that necessitated agglomeration in the first place.

If binder-containing agglomerates are to be used, such agglomerates canbe made by the methods described in, for example, U.S. Pat. No.4,161,516 and GB Patent 1,520,247 which disclose the use of certainbinding materials, including water, for the production of agglomeratesfor oral inhalation According to the processes described therein priorto agglomeration, the moisture content of certain “self agglomerating”or hygroscopic micronized drugs are elevated. After the micronizedpowder has been elevated to the desired water content level, it isagglomerated. Non-hygroscopic materials must be bound with moretraditional binders as described therein Similarly, WO 95/05805discloses a process for forming agglomerates where a mixture ofhomogeneous micronized materials are treated with water vapor toeliminate any convertible amorphous content which may destabilize at alater point. After treatment with water vapor, the now crystallinematerial is agglomerated. However, this application warns that if thevapor exposure is conducted after agglomeration, the product is “uselessin an inhalation device.”

The effect of moisture on the tableting characteristics of anhydrouslactose is discussed in Sebhatu, Elamin and Ahlneck, “Effect of MoistureSorption on Tableting Characteristics and Spray Dried (15% Amorphous)Lactose,” Pharmaceutical Research, Vol. 11, No. 9, pages 1233-1238(1994). The article does not, however, discuss the formation ofagglomerates, or the production of agglomerates which can yield anacceptable “fine particle fraction,” also known as a “respirablefraction” when administered as part of oral inhalation therapy.

The Sebhatu et al. article uses a method for determining amorphouscontent which is more fully described by T. Sebhatu, M. Angberg and C.Ahlneck, “Assessment of the Degree of Disorder in Crystalline Solids byIsothermal Microcalorimetry,” International Journal of Pharmaceutics,Vol. 104, pages 135-144 (1994). An isothermal microcalorimeter is usedto determine the specific heat of crystallization for totally amorphouslactose, and then the “percent disorder” (denoted herein, for purposesof the present invention, “percent convertible amorphous content”) isdetermined by dividing the specific heat of crystallization for apartially amorphous sample by the value previously obtained for thetotally amorphous material, then multiplying by 100. The equipmentdescribed for making these measurements is satisfactory for use in thepresent invention.

SUMMARY OF THE INVENTION

The present invention provides an improved agglomerate and a process formaking same. By design, the present invention takes advantage of the useof a solid binder in combination with fine drug particles and theamorphous characteristics which can be imparted to the solid binderand/or the drug. This occurs just when others would seek to eliminatesuch characteristics. The present invention also results in uniquecrystalline agglomerates of a first material and a solid binder whichare free-flowing, sufficiently bulky and sufficiently stable to behandled, metered and delivered, even in extremely small doses. At thesame time, the interparticulate bond strength of the agglomerates issufficiently fragile to allow the agglomerates to break apart duringadministration through an inhaler so as to provide an acceptable fineparticle fraction. All of this is accomplished substantially without theuse of an additional, more conventional binder.

In particular, the present invention provides a process of producingagglomerates. The process includes providing particles of at least onefirst material, generally a pharmacologically active agent, andproviding particles of at least one solid binder. At least one of thesetwo particles, the drug or the solid binder, includes as part thereof, apreselected amount of a convertible amorphous content which issufficient to, upon crystallization thereof, allow for the formation ofgenerally crystalline, agglomerates. The predetermined convertibleamorphous content of the binder and/or the drug is capable of beingconverted to a crystalline form upon exposure to a preselected stimuluswhich includes, among other things, humidity.

The particles are then agglomerated while maintaining the preselected orpredetermined amount of convertible amorphous content. Afteragglomeration is complete, the convertible amorphous content within theagglomerates is exposed to the preselected stimulus and is converted toa crystalline form. By “crystalline,” it is understood that theagglomerates of the present invention can still contain some amorphouscontent, predominantly non-convertible amorphous phase with or withoutsome amount of unconverted convertible amorphous content. The latter isto be minimized. Without wishing to be bound by any particularscientific theory it is believed that the conversion of the convertibleamorphous content creates crystalline bonds between the particles. Thesebonds are strong enough to preserve the integrity of the agglomeratesduring handling, storage and metering. However, they are soft enough tobe overcome by commercially available inhalers so as to provide anacceptable fine particle fraction upon dosing.

It is an important aspect of the present invention that the agglomeratescontain a certain content of convertible amorphous content duringformation. “Convertible” means that the amorphous content, when exposedto certain predetermined or preselected stimuli, will convert fromamorphous to crystalline form. This convertible amorphous content can bepresent as part of the drug part of the solid binder, or both. Thedistribution of the amorphous content on the particles is generallyunimportant so long as sufficient convertible amorphous content ispresent, preferably substantially homogeneously, throughout the system.

The fact that the solid binder may or may not contain any convertibleamorphous content is not important in and of itself. In such instances,the solid binder still imparts certain advantageous properties to theresulting agglomerates in terms of their ability to flow freely, theirbulk density, their strength and the ability to retard hang-up.

In a more preferred embodiment, the present invention provides a methodof producing agglomerates of a pharmacologically active agent includingthe steps of providing of at least one pharmacologically active agenthaving an average particle size of below about 10 μm and at least onesolid binder. Preferably, the majority of the solid binder also existsas particles of less than about 10 μm Generally, the binder has apreselected amount of convertible amorphous content which is sufficientto allow for the formation of agglomerates with the pharmacologicallyactive agent upon crystallization by exposure to a preselected stimulussuch as atmospheric moisture. The next step involves forming asubstantially homogeneous mixture of the panicles while maintaining thepreselected amount of convertible amorphous content. The mixture is thenagglomerated while still maintaining the preselected amount of amorphouscontent. Finally, the convertible amorphous content of the solid binderand/or drug within the agglomerates is converted to a crystalline formby exposure to the preselected stimulus. The resulting agglomerates arefree-flowing and are characterized by bridges or bonds between theparticles such as, for example, between the pharmacologically activeagent and the solid binder, (or even between the particles of the solidbinder themselves), which are strong enough to withstand handling, butweak enough to allow for the delivery of an acceptable fine particlefraction of free particles of the pharmacologically active agent.

The result of this preferred aspect of the present invention is thecreation of a dosage form of a pharmacologically active agent useful aspart of oral and/or nasal inhalation therapy. The dosage form includesagglomerates of particles of the pharmacologically active agent andparticles of crystalline solid binder. The particles preferably have anaverage particle size of 10 μm or less.

The ratio of drug to binder in the agglomerate can vary widely dependingupon the amount of drug to be administered, the fine particle fractiondesired and the amount of and relative distribution of, convertibleamorphous content present as part of the drug and/or binder. In fact,the ratio of drug to binder can range from between about 1000:1 to1:1000 (drug:binder). However, preferably, the drug and binder arepresent in a ratio of between 100:1 to 1:500 and even more preferablybetween 100:1 to 1:300.

The agglomerates generally range in sizes from between about 100 toabout 1500 μm and an average size of between 300 and 1000 μm. The bulkdensity of the resulting agglomerates is between about 0.2 and about 0.4g/cm³. Preferably the ratio of drug to solid binder ranges from betweenabout 20:1 to about 1:20 and most preferably 1:3 to 1:10. Theagglomerates also preferably have an average size of between about 300and about 800 μm and more preferably between about 400 and about 700 μm.

In another aspect of the present invention there is provided anintermediate agglomerate useful for producing a free-flowing crystallineagglomerate dosage form of a pharmacologically active agent. Theintermediate agglomerate includes particles of a pharmacologicallyactive agent and particles of solid binder, preferably anhydrouslactose. The binder and/or the drug particles include a preselectedamount of convertible amorphous content which is sufficient to allow forthe formation of crystalline agglomerates upon exposure to a preselectedstimulus. The particles of pharmacologically active agent and particlesof the binder have an average particle size of about 10 μm or below, andeach is provided in a ratio of between about 100:1 and about 1:500 andeven more preferably between about 100:1 and about 1:300. The resultingagglomerates range in size from between about 100 μm to about 1500 μmand have an average size of between 300 and 1000 μm. Their bulk densitygenerally ranges from between about 0.2 and about 0.4 g/cm³.

These intermediate agglomerates are too weak to withstand normalhandling and thus they are not suitable for a dosage form. They alsohave a relatively high rate of hang up in the nozzle of an inhaler. Suchagglomerates are also not stable. Over time, they will converts in anuncontrolled manner, to a crystalline form. This yields a higher levelof variability in terms of bond strength and dosing uniformity. However,these amorphous agglomerates are very useful in the formation ofcrystalline dosage forms in which at least substantially all of theconvertible amorphous content is converted to a crystalline form byexposure to a preselected stimulus.

A particularly preferred aspect of the present invention is theprovision of a method of ensuring a higher level of dosing uniformityfor very small doses of orally inhaled pharmacologically active agentsor drugs (about 400 μg of drug or below). The method includes metering adose of an agglomerated pharmacologically active agent as previouslydescribed and administering that dose of agglomerated pharmacologicallyactive agent to a patient in need thereof.

The present invention also provides a metered dose of apharmacologically active agent useful for administration by oralinhalation therapy. The metered dose can vary widely in size; includingup to about 50,000 μg of the pharmacologically active agent perinhalation. The ability to accommodate such a wide range of dosinglevels is a direct result of the advantages which inure from the use ofthe present invention to manufacture agglomerates. However, the presentinvention is most useful in the context of ver small doses including upto about 400 μg of particulate pharmacologically active agent with thebalance being lactose binder. More particularly, the dose contains about100 kg of pharmacologically active agent or less. It is these smallerdosing levels which are the most demanding on dosage forms.

Oral inhalation of a pharmacologically active agent, as previouslynoted, can be demanding, not only on dosing equipment, but also onformulations. The dosage form appears to need to simultaneously meet anumber of criteria, many of which were thought to be mutually exclusive.For example, it is very important that the agglomerates be formed in ahighly repeatable, consistent manner with very little variation in termsof size, drug content and interparticle to bond strength. Theagglomerates must also be sufficiently solid to allow them to be worked,sieved, spheronized and otherwise manipulated without falling apart. Atthe same time, the agglomerates must be sufficiently weak so as to allowthem to break apart during inhalation and yield, to the extent possible,small, free particles of drugs in a manner which is therapeuticallyeffective. For another example, the agglomerates must be sufficientlyfree-flowing to allow them to be loaded into an inhaler, and meteredthrough the inhaler and delivered, with as little residue being retainedas possible. However, forming agglomerates of inherently free-flowingmaterials can be difficult.

One of the most interesting aspects of the present invention is therealization that attempting to balance these often competing performancecriteria is neither possible nor necessary. Instead, the invention usescertain properties when those properties are advantageous. Then, justwhen those same attributes would become liabilities, the agglomerate ischanged fundamentally to eliminate those properties entirely. In theirplace, a new crystalline agglomerate is realized. This new agglomerateretains none of those properties of the former agglomerates which wereuseful for agglomerate formation, but detrimental to handling, measuringand administering.

Instead, the new agglomerates, after conversion of the convertibleamorphous content of the solid binder and/or the drug, are free flowingand very consistent in terms of agglomerate size and size distribution.Furthermore, the agglomerates are sufficiently rugged to allow them tobe handled metered, and even dropped white within an inhaler without theadverse consequences found in the prior art. At the same time, when usedin combination with an inhaler that can generate sufficient force, thestructural integrity of these rugged agglomerates can be interruptedsufficiently so as to provide an acceptable fine particle fraction.

Therefore, in accordance with another aspect of the present invention,there is provided a crystalline agglomerate of a drug with an averageparticle size of 10 μm or less and particles of a solid binder. Theseparticles are bound together as a result of the conversion at a portionof a convertible amorphous region of either the drug, the binder, orboth. No additional binder is required. These agglomerates are providedin combination with a nasal or oral inhaler which is configured so as toprovide a fine particle fraction of drug particles of at least 10%. Ingeneral, the agglomerates which result have a crush strength of betweenabout 50 mg and about 5,000 mg. More preferably, the crystallineagglomerates in accordance with the present invention have a crushstrength of between about 200 mg and about 1500 mg. Thus, the inhalerused for dosing these agglomerates will have to provide, as a minimum,sufficient force to overcome the inherent strength of the agglomerate soas to result in a fine particle fraction of at least about 10% or more.This means that at least 10% of the drug will be reduced to a fineparticle fraction of particles having a size of 6.8 μm or less. Itshould come as no surprise that if an inhaler is configured to provideat least a 10% fine particle fraction of the drug when the agglomeratestrength is 5,000 mg, the same inhaler will provide a much greater fineparticle fraction if used in combination with agglomerates in accordancewith the present invention having a strength of, for example, 500 mg.

It has also been found that by providing a solid binder having a similarrange of particle sizes when compared to the particle size of theparticles of drug, it is possible to obtain a substantially homogeneousdistribution of drug in each metered dose, even when the metered dosesof drug are as small as about 400 μg or below.

In sum, it has been found that by converting the amorphous content ofthe binder or drug to a crystalline form within the pre-formedagglomerate, once agglomeration is complete, one can impart desirableproperties. When the amorphous content of the agglomerates is convertedto crystalline form, the agglomerates become stable. They are, indeed,less sensitive to factors such as humidity and temperature. Thecrystalline material is also free-flowing and exhibits reduced hang uprelative to the same agglomerates prior to conversion. It is easier toload into and empty from a dose hole and, therefore, provides forconsistent metering. This coupled with high stability and homogeneitymakes consistent dosing of very small doses possible.

Thus it has been found that, through the present invention, it ispossible to provide materials which are ideally suited for agglomerationjust when it is necessary to agglomerate such materials and it is alsopossible to produce agglomerates which are ideally suited foradministering pharmacologically active substances through an oralinhalation system.

Another important aspect of the present invention is a change in theconventional perception of the amorphous content of particles. Theindustry has long known of the amorphous character imparted to certainmaterials by such processes as micronizing, spray drying, freeze dryingand ball milling. Some degree of amorphous character is unavoidablyimparted upon materials when the particle size is reduced using suchtechniques. However, because of the variability that can result fromsuch amorphous materials, the industry has long sought a way to minimizeor eliminate the creation of amorphous content during microparticleformation.

In fact, that is the very point of WO 95/05805. That PCT applicationseeks to form, as much as possible, a homogenous mixture of particles ofas uniform characteristics as possible so as to insure the production ofagglomerates having a more tightly controlled size. The theory appearsto be that if one can insure a homogeneity in terms of particle size,mixture of particles and crystallinity, is easier to control theresulting size and composition of agglomerates. Therefore, moisture isadded to the particles, prior to agglomeration, to insure that theirentire convertible amorphous content is converted to crystalline form.

In accordance with the present invention, however, it has been foundthat the amorphous character of the drug and/or binder can be harnessedto the formulator's advantage. By using the amorphous content of themixture as the binder, one can eliminate the need for additionalbinders. This can only be accomplished, however, where agglomerationoccurs prior to exposure of significant quantities of atmosphericmoisture. Once the particulate has been exposed to moisture, theconversion of the convertible amorphous content will prevent a solidstate agglomeration and a formation of direct intercystalline bonds.

Moreover, it has been found that merely imparting such amorphous contentupon particles is not sufficient. Certainly, it has long been known tomicronized drugs. However, because of many drugs natural stability, theycannot be readily transformed to crystalline agglomerates as discussedherein. Rather, it has been discovered that by imparting a certainamount of amorphous character to a solid binder, a binder which iscapable of being readily re-converted to a crystalline form, theadvantages of the present invention can be realized. It has beendiscovered that the use of a solid metastable material as a binderprovides advantages both when the binder is in its amorphous form andagain when it is in its crystalline form, so long as the various formsare intentionally used at the right time.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph illustrating the water uptake of agglomerates of thepresent invention when exposed to humidity before and after beingsubjected to conversion.

FIG. 2 is a block diagram illustrating a manufacturing scheme foragglomerates of either lactose alone or mometasone furoate and lactose.

FIG. 3 is a graph illustrating the results of a 122 cm (48 inch.) droptest wherein: ∘ is inhaler 1, • is inhaler 2,

is inhaler 3, ▾ is inhaler 4,

is inhaler 5, ▪ is inhaler 6,

is inhaler 7, ▴ is inhaler 8, ⋄ is inhaler 9, and

is inhaler 10.

FIG. 4 is a graph illustrating the results of a control for a 122 cm (48inch.) drop test wherein: ∘ is inhaler 1, • is inhaler 2,

is inhaler 3, ▾ is inhaler 4,

is inhaler 5, ▪ is inhaler 6,

is inhaler 7, ▴ is inhaler 8, ⋄ is inhaler 9, and ♦ is inhaler 10.

DETAILED DESCRIPTION OF THE INVENTION

An agglomerate in accordance with the present invention is a bound massof small particulates. The agglomerates include at least one firstmaterial and at least one solid binder. The first material, inaccordance with the present invention can be anything as, indeed, thepresent invention can be used broadly to make free-flowing agglomeratesfor any application including, medicine, cosmetics, food and flavoring,and the like. However, preferably, the first material to is apharmacologically active agent or drug which is to be administered to apatient in need of some course of treatment. The pharmacologicallyactive agent may be administered prophylactically as a preventative orduring the course of a medical condition as a treatment or cure.

Most preferably, in accordance with the present invention, thepharmacologically active agent or drug is a material capable of beingadministered in a dry powder form to the respiratory system, includingthe lungs. For example, a drug in accordance with the present inventioncould be administered so that it is absorbed into the blood streamthrough the lungs. More preferably, however, the pharmacologicallyactive agent is a powdered drug which is effective to treat somecondition of the lungs or respiratory system directly and/or topically.Particularly preferred pharmacologically active agents in accordancewith the present invention include, without limitation, corticosteroidssuch as: mometasone furoate; beclomethasone dipropionate; budesonide;fluticasone; dexamethasone; flunisolide; triamcinotone;(22R)-6α,9α-difluoro-11β,21-dihydroxy-16α,17α-propylmethylenedioxy-4-pregnen-3,20-dione;tipredane and the like. β-agonists (including β₁ and β₂-agonists)including, without limitation, salbutamof (aibuterol), terbutaline,salmeterol, and bitolterol may also be administered. Formoterol (alsoknown as eformoterol) e.g., as the fumarate or tartrate, a highlyselective long-lasting β₂-adrenergic agonist having bronchospasmolyticeffect, is effective in the treatment of reversible obstructive lungailments of various genesis, particularly asthmatic conditions. Anotherlong-acting β-agonist which can be administered in accordance with thepresent invention is known as TA-2005, chemically identified as2(1H)-Quinolinone,8-hydroxy-5-[1-hydroxy-2-[[2-(4-(methoxyphenyl)-1-methylethyl]amino]ethyl]-monohydrochloride,[R—(R*,R*)]— also identified by Chemical Abstract Service RegistryNumber 137888-11-0 and disclosed in U.S. Pat. No. 4,579,854, the text ofwhich is hereby incorporated by reference. Anticholinergics such asipratropium bromide and oxitropium bromide may be used. So, too cansodium cromoglycate, nedocromil sodium and leukotriene antagonists suchas zafirlukast and pranlukast. Bambuterol (e.g. as hydrochloride),fenoterol (e.g. hydrobromide), clenbuterol (e.g. as hydrochloride), toprocaterol (e.g. as hydrochloride), and broxaterol are highly selectiveβ₂-adrenergic agonists can be administered, Several of these compoundscould be administered in the form of pharmacologically acceptableesters, salts, solvates, such as hydrates, or solvates of such esters orsalts, if any. The term is also meant to cover both racemic mixtures aswell as one or more optical isomers. The drug in accordance with thepresent invention can also be an inhalable protein or a peptide such asinsulin, interferons, calcitonins, parathyroid hormones, granulocytecolony-stimulating factor and the like. “Drug” as used herein may referto a single pharmacologically active entity, or to combinations of anytwo or more, an example of a useful combination being a dosage formincluding both a corticosteroid and a β-agonist. A preferredpharmacologically active agent for use in accordance with the presentinvention is mometasone furoate.

To be topically effective in the lungs or the upper and/or lower airwaypassages, it is important that the pharmacologically active agent bedelivered as particles of about 10 μm or less. See Task Group on LungDynamics, Deposition and Retention Models For Internal Dosimetry of theHuman Respiratory Tract, Health Phys., 12, 173, 1966. The ability of adosage form to actually administer free particles of thesetherapeutically effectively sized particles is the fine particlefraction. Fine particle fraction is, therefore, a measure of thepercentage of bound drug particles released as free particles of drughaving a particle size below some threshold during administration. Fineparticle fraction can be measured using a multi-stage liquid impingermanufactured by Copley Instruments (Nottingham) LTD using themanufacturer's protocols. In accordance with the present invention, anacceptable fine particle fraction is at least 10% by weight of the drugbeing made available as tree particles having an aerodynamic particlesize of 6.8 μm, or less, measured at a flow rate of 60 liters perminute.

The amount of drug administered will vary with a number of factorsincluding, without limitation, the age, sex, weight, condition of thepatient, the drug, the course of treatment, the number of doses per dayand the like. For mometasone furoate, the amount of drug delivered perdose, i.e. per inhalation, will generally range from about 10.0 μg toabout 10,000 μg. Doses of 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg,175 μg, 200 μg, 250 μg, 300 μg, 400 μg and/or 500 μg are preferred.

The drug may include some or all of the convertible amorphous content ofthe agglomerates as discussed herein.

The solid binder in accordance with the present invention can be anysubstance which can be provided in, or reduced to, a particle size whichis roughly congruent with the size of the particles of thepharmacologically active agent as previously described. For example,agglomerates of mometasone furoate anhydrous USP will preferably beprovided having particles of at least 80%≦5 μm and at least 95%≦10 μm(measured by volume distribution). The solid binder, such as anhydrouslactose, NE will be provided having particles of at least 60%≦5 μm, atleast 90% under 10 μm, and at least 95%≦20 μm. The average particle sizeis roughly the same for both and is less than 10 μm.

When in a crystalline form, i.e. when all, or almost all of theconvertible amorphous content of the solid binder convened to acrystalline form, the binder must be stable, capable of supporting andmaintaining an agglomerate and binding particles of therapeuticallyactive agents such that same can be released as a fine particle fractionof particles. The binder must also impart to the crystalline agglomeratea desired range of properties including bulk density, strength, afree-flowing character, and storage stability.

Preferably, the convertible amorphous content of the solid binder, ifindeed, it contains some or all of the convertible amorphous content ofthe agglomerate, will convert from its amorphous form to its crystallineform upon exposure to a preselected or predetermined stimulus such asatmospheric moisture in the form of humidity. However, materials whichmeet all of the foregoing criteria and will convert responsive to otherpreselected stimuli such as, for example, temperature, radiation,solvent vapor and the like may also be used. Preferred solid bindersinclude polyhydroxy aldehydes, polyhydroxy ketones, and amino acids.Preferred polyhydroxy aldehydes and polyhydroxy ketones are hydrated andanhydrous saccharides including, without limitation, lactose, glucose,fructose, galactose, trehalose, sucrose, maltose, raffinose, mannitol,melezitose, starch, xylitol, mannitol, myoinositol, their derivatives,and the like.

Particularly preferred amino acids include glycine, alanine, betaine andlysine.

Where the drug is completely crystalline, or where it contains onlynon-convertible amorphous content, the solid binder must provide all ofthe amorphous content of the agglomerate system and vice versa. Neitherthe solid binder material, nor the drug need naturally have such anamorphous content, so long as such an amorphous content can bereversibly imparted thereto.

It is possible that the drug, the binder or both contains a certainpercentage of amorphous content which is non-convertible or stable underthe conditions of use and storage, as well as when the preselectedstimuli is applied. This stable amorphous content is not part of theconvertible amorphous content previously discussed. As is generally thecase, this stable amorphous content has some role in interparticulatebinding. However, it will not contribute to the interparticulate bondingwhich results from the conversion between amorphous and crystallinematerials in accordance with the present invention.

Therefore, in certain formulations such as those using, for example,mometasone furoate, all of the convertible amorphous content iscontributed by the solid binder. As such, sufficient solid binder mustbe provided to impart enough convertible amorphous content to theagglomerate system. However, with another drug such as, for example,albuterol sulfate, which itself can contain convertible amorphouscontent, it may be possible to use a binder with no amorphous content orto use a mixture of a solid binder containing a certain lower percentageof amorphous content along with albuterol. Too much convertibleamorphous content can result in agglomerates which are bound too tightlyto yield the desirable fine particle fraction. Generally, the amount ofamorphous content in the system should range from between about 1 toabout 50% by weight and more preferably between about 3 and 30% byweight. Most preferably, the amount of convertible amorphous content inthe system will range from between about 5 to about 25% by weight. Ofcourse, it is equally acceptable to characterize the amorphous contentof either the binder or the drug, individually, in terms of the percentof amorphous content in the system. Thus, where the binder contains thetotal convertible amorphous content, and where the binder contains a 20%amorphous content and is provided in the 1:1 ratio by weight with thedrug, the total convertible amorphous content in the system will be 10%by weight.

Some convertible amorphous character can be imparted upon certainmaterial, during the course of reducing the particle size thereof. Thus,for example, if anhydrous lactose is micronized in a micronizer such asMICRON-MASTER® Jet Pulverizer available from the Jet Pulverizer Co.,Palmyra, N.J., it is possible to obtain not only particles of thedesired size, but also to impart a certain amount of amorphous content.This can also be accomplished using other traditional microparticlegenerating devices such as milling, spray drying or ball milling. SeeBriggner, Buckton, Bystrom and Darcy, “The use of isothermalmicrocalorimetry in the study of changes in crystallinity induced duringthe processing of powders,” International Journal of Pharmaceutics, 105(1994), pp. 125-135. However, where others have tried to minimize thedegree of amorphous content generated and have considered this amorphouscontent to be an unfortunate, but generally unavoidable, side effect ofparticle size reduction, the present invention seeks to encourage acertain amount of amorphous content.

The present invention also seeks to control and maintain that amorphouscharacter of the solid binder and/or the drug until a specified time inthe agglomeration process. To this end, certain steps are taken toimpart a preselected amount of amorphous character and to maintain theamorphous character of the solid binder and/or the drug. For example,when anhydrous lactose is pulverized using a Jet Pulverizer aspreviously discussed, pulverization is carried out under considerablepressure such as, for example, between about 50 and about 120 psig (3.45to 8.27×10⁵ newton/m²). About 80-100 psig (5.51 to 6.89×10⁵ newton/m² ispreferred. The use of such high pressures results in a particularlyviolent particle formation environment and generally increases theamount of amorphous content. Moreover, applicants preferably use drycompressed nitrogen gas to pulverize the solid binder, as applicantshave discovered that the exposure of the amorphous content to humidityduring particle formation can act to reconvert the amorphous contentback to a crystalline form prematurely.

Of course, it is also possible to impart an amorphous surface toparticles of a solid binder and/or drug which is already of correctparticle size or to use particulate which is inherently amorphous incharacter and can be converted to a crystalline form.

Once sufficient convertible amorphous content is present, that amorphouscharacter must be maintained until such time as it is desirable toconvert the particles into completely crystalline form. For solidbinders or drugs, such as lactose, which are sensitive to humidity, thiscan be accomplished by processing and storing under low humidityconditions.

Preferably, the micronized materials are subsequently stored and/orprocessed under conditions of less than about 30% relative humidity(“RH”) and more preferably, less than 20% RH at 21° C. By this it ismeant that the micronized materials are processed and stored at anatmospheric moisture content which is equal to that of an atmosphere of30% RH at 21° C. or less. Exact amounts of moisture present in theatmosphere at various temperatures can be derived from Table 5.27, “Massof Water Vapor in Saturated Air,” at page 5.150 of John A. Dean, Lange'sHandbook of Chemistry, Fourteenth Ed., McGraw-Hill, Inc. New York(1992). It is particularly preferable to store any materials containingconvertible amorphous content under humidity conditions of less than 10%RH at 21° C. and, most preferably, as close to zero relative humidity aspracticable. All processing may be carried out at any temperature.However, processing is usually more conveniently carried out between 0°C. and 38° C.

Generally, any method of agglomerating the solid binder and thepharmacologically active agent, which can be accomplished withoutconverting the amorphous content of the solid binder to a crystallineform, prematurely, and which does not require the use of additionalbinder, can be practiced in accordance with the present invention. Forthis reason, one can generally not practice the agglomeration processesdisclosed in the aforementioned U.S. Pat. No. 4,161,516 as water and/ormoisture are added as a binder prior to agglomeration. This would causethe premature conversion of some or all of the amorphous content to acrystalline form which would actually retard agglomerate formation andlead to variability. This variability could also cause the formation ofagglomerates which are too hard and strong. Even when such agglomeratesare administered using an inhaler which provides a particularly violentdispensing action, these agglomerates may not yield an acceptable fineparticle fraction.

It is important that the process produce agglomerates ranging in size isfrom between about 100 to about 1500 μm. The agglomerates generally havean average size of between about 300 and about 1,000 μm. Morepreferably, the agglomerates have an average size of between about 400and about 700 μm. Most preferably, the agglomerates will have an averagesize of between about 500 and 600 μm. The resulting agglomerates willalso have a bulk density which ranges from between about 0.2 to about0.4 g/cm³ and more preferably, between about 0.29 to about 0.38 g/cm³.Most preferably, the agglomerates will have a bulk density which rangesfrom between about 0.31 to about 0.36 g/cm³.

It is also important to the dosing of the pharmacologically active agentthat the agglomeration process yield a relatively tight particle sizedistribution. In this context, particle size refers to the size of theagglomerates. Preferably, no more than about 10% of the agglomerates are50% smaller or 50% larger than the mean or target agglomerate size. Thusfor a desired agglomerate of 300 μm, no more than about 10% of theagglomerates will be smaller than about 150 μm or larger than about 450μm.

A preferred method of preparing the agglomerates in accordance with theinvention which meets al of the foregoing criteria involves mixingpreselected amounts of one or more pharmacologically active agent(s) andthe micronized, amorphous content containing, dry solid binder in aratio of between about 100:1 and about 1:500 and even more preferablybetween about 100:1 and about 1:300 (drug:binder) and preferably a ratioof between 20:1 to about 1:20. Most preferably, the drug would beprovided in an amount of 1:3 to about 1:10 relative to the amount of thesolid binder.

These particles are then preferably mixed in some form of mechanicalmixing device. Preferably, mixing will result in substantialhomogeneity. Of course, it may not be possible for one to obtainabsolute homogeneity. However, a tolerance of ±10% is acceptable duringblending and ±5% is acceptable during agglomeration, Blending suchingredients, in fine particle form, may be a challenge in and of itself.Blending can be accomplished, for purposes of example only, using aPatterson-Kelly V-shape blender having a pin intensifier bar.Preferably, the blending procedure is carried out in the clean room,and, as previously noted, the humidity and temperature of the roomshould be controlled. At 21° C. and 20% RH for example, conversion ofthe amorphous content is sufficiently slow to allow blending. Dependingupon the size of the batch, blending can be accomplished within betweenabout 3 and 15 minutes total. If the mixture of micronized drug andsolid binder will not be further processed immediately, it should againbe stored under low humidity and low temperature conditions.

For a particularly small amount of drug as relative to the solid binder,the conventional blending technique may not result in an acceptablyhomogeneous mixture. In this case, the following approaches may be used:(1) blending of the drug or drugs and the solid binder beforemicronization; (2) when a mixture of pharmacologically active agents isused, and particularly when one is present in significantly largeramounts than the other, blending the to agents together, micronizing theblend and then blending with micronized solid binder having aconvertible amorphous content; and/or (3) forming microspheres by spraydrying, such as: (a) dissolving or suspending the drug in an aqueoussolution of a diluent or carrier, such as lactose, spray drying and thenmixing the resulting microspheres with micronized solid binder having aconvertible amorphous content; or (b) spray drying a nonaqueous solutionor suspension of drug, containing suspended, micronized diluent orcarrier particles, such as lactose, then mixing with solid binderparticles having a convertible amorphous content. In fact, even withlarger amounts of drug, it may be desirable to employ the firstapproach.

From the blender, the mixed particles are poured into a conventionalscreen/pan combination for agglomerate formation. The particles can nowbe thought of as an agglomeration as they no longer retain as much oftheir individual identity. They are not “agglomerates” as describedherein as they are not smaller, individualized collections of particlesof generally spherical shape and/or greater density.

Screen and pan are then rotated in an eccentric circular motion in aplane parallel to the ground. This can be done manually or using ascreen shaking device. An intermittent tapping is appliedperpendicularly to the top of the pan which forces or meters materialsthrough the screen into the pan below where the eccentric motion of thepan encourages agglomerate formation as defined previously. Theagglomerates are also simultaneously spheronized. Of course, thisagglomeration procedure, as with any agglomeration procedure inaccordance with the present invention, must be carried out under lowhumidity conditions to prevent the unwanted, premature conversion of theamorphous content of the solid binder to crystalline form.

After the agglomerates are formed and properly sized by, for example,pouring through another screen, they can be exposed to a preselectedstimuli, such as higher humidity, to cause the substantially completeconversion of the convertible amorphous content contained within theagglomerates to a crystalline form.

Of course, the higher the humidity, the less the amount of timenecessary for exposure. However, a somewhat gradual and controlledconversion is preferred as the strength of the agglomerates is to betightly controlled. Agglomerates containing convertible amorphouscontent can be exposed to relative humidity of between about 30% andabout 80% (at 25° C.) for a time period which is sufficient to convertthe entire amorphous content. More preferably, the convertible amorphouscontent is converted by exposure to an atmosphere having a water contentequal to a relative humidity of between about 40% and about 60%(measuring the relative humidity at about 25° C.). This is particularlyuseful when the solid binder is anhydrous such as anhydrous lactose. Theamount of time can vary dramatically with the size and density of theagglomerates and the surface area of exposure. For example, placing athin layer of agglomerates on a flat open tray will yield a much fasterconversion overall than placing the same quantity of agglomerate in anarrow jar. In certain cases, the length of exposure need be on theorder of tens of minutes. In other instances, one to two days may berequired.

Because, preferably, the exposure is controlled to relative humiditiesof 65% or below (at 25° C.), there is relatively little concern aboutoverexposure So long as sufficient time is provided to allow all of theconvertible amorphous content of the agglomerates to convert tocrystalline form, the fact that additional exposure may take place isgenerally not of any consequence. If humidity levels above about 65% areused, however, then the water vapor can actually act as a binder. Whilethe use of water as a binder is well known, it is detrimental to theability to generate a fine particle fraction, particularly when used incombination with the principal mode of binding described herein; namelycrystalline binding. Therefore, it is still desirable to limit theexposure of the agglomerates to elevated humidity levels beyond thepoint necessary for complete conversion. After conversion, theagglomerates have an interparticulate bonding strength which ismeasurably greater than the interparticulate bonding strength prior toconversion.

The agglomerates that result are, as previously described, generallycrystalline in nature, free-flowing, rugged and resistant to hang up.These agglomerates can be stored, handled, metered and dispensed whilemaintaining their structural integrity. The agglomerates also have avery desirable and consistent size and size distribution. Perhaps mostimportantly, the crystalline agglomerates of the present invention havesufficient strength to allow them to be handled and abused. At the sametime, the agglomerates remain soft enough to be broken sufficientlyduring dosing so as to provide an acceptable fine particle reaction. Ingeneral, the agglomerates have a strength which ranges from betweenabout 50 mg and about 5,000 mg and most preferably between about 200 mgand about 1,500 mg. The crush strength was tested on a Seiko TMA/SS 120CThermomechanical Analyzer available from Seiko Instruments, Inc. Tokyo,Japan, using procedures available from the manufacturer. It should benoted that strength measured in this manner is influenced by the qualityand extent of the interparticulate crystalline bonding described herein.However, the size of the agglomerates also plays a role in the measuredcrush strength. Generally, larger agglomerates require more force tocrush than do the smaller particles.

When agglomerates produced in accordance with the protocol reported inExample 1 were dosed at 100 μg per inhalation using a powder inhaler asdescribed in WO 94/14492 assigned to Schering Corporation, sufficientlyviolent force was generated so as to break up the agglomerates enough toyield the desired level of free drug particles having a size of about6.8 μm or less. Of course, the degree of force which must be generatedwhile the agglomerates are dispensed is dependent upon the internal bondstrength of the agglomerates. The greater the bond strength, the greaterthe amount of force which will be required to yield an acceptable fineparticle fraction. The agglomerates of the present invention, while toostrong and stable for certain inhalers are, nonetheless, useful in othercommercially available inhalers and, when dispensed from same, anacceptable fine particle fraction results. Such inhalers include,without limitation, Schering's inhaler as identified above, Diskhaler(Allen & Hanburys), Accuhaler (Allen & Hanburys), Diskus (Glaxo), Spiros(Dura), Easyhaler (Orion), Cyclohaler (Pharmachemie), Cyclovent(Pharmachemie), Rotahaler (Glaxo), Spinhaler (Fisons), FlowCaps(Hovione), Turbospin (PH&T), Turbohaler (Astra), EZ Breath (NortonHealthcare/IVAX), MIAT-HALER (Miat), Pulvinal (Chiesi), Ultrahaler(Fisons/Rhone Poulenc Rorer), MAG-Haler (GGU), Prohaler (Valois), Taifun(Leiras), JAGO DPI (JAGO), M L Laboratories' DPI (M L Laboratories).

The inhaler must be capable of producing sufficient force to break upwhatever agglomerate is used so as to produce an acceptable fineparticle fraction. Therefore, an agglomerate having a crush strength of1,000 mg as measured in the manner described herein, must be used incombination with an inhaler that can apply sufficient force to ensurethat at last a 10% fine particle fraction results from each dosetherefrom.

As shown in FIG. 1, mometasone:anyhydrous lactose agglomerates of aratio of 1:5.8 (by weight) were exposed to 50% relative humidity at 25°C. both before and after conversion. The graph using the unbroken line(I) demonstrates the moisture uptake of the agglomerates when exposed tohumidity before the agglomerates are converted to crystalline form.Moisture is absorbed very quickly reaching a maximum point. At thatpoint, conversion to the crystalline form takes place. As the result ofthat conversion, water is actually expelled and the overall moisturecontent drops. By the same token, once agglomerates which have beenconverted are exposed to moisture, they may absorb a small amount to ofmoisture, but thereafter, moisture uptake is flat. See broken line (II).Amongst other things, FIG. 1 demonstrates the resulting stability of theagglomerates which are formed in accordance with the present invention.

The discovery and use of the increasing bond strength of the crystallineagglomerates is significant for a number of reasons. First the resultingagglomerates are free-flowing, stable, and able to be handled andpackaged appropriately. Second, the agglomerates provide the necessaryhomogeneity and bulk density to allow them to be consistently loadedinto the dose hole of an inhaler, even in particularly small doses. Thusthe crystalline agglomerates can be accurately metered, measured anddelivered. This is aptly demonstrated in FIG. 2. When the process of thepresent invention was carried out on lactose alone, and when humiditywas added to the lactose prior to agglomeration, the resulting lactoseagglomerate proved to be too soft to handle. Significant problems inrepeatable dosing would thus be realized. These same results wereobserved when mixtures of drug and lactose were exposed to humidityprior to agglomeration.

In tact, in formulating a batch in accordance with the present inventionas described in Example 1, anhydrous lactose was used that had alreadybeen converted. That fact was not known at the time. When the resultingagglomeration protocol did not yield the desired results, the cause wasinvestigated. The prior conversion of the lactose was subsequentlydiscovered. Thus, it is important to maintain the convertible amorphouscontent of the drug and/or binder in that state until after theformation of agglomerates as described herein.

In another experiment also illustrated in FIG. 2, mometasone containingagglomerates were filled into an inhaler prior to stabilization withhumidity. The final product was not stable and provided poor dosedelivery due to high hang up in the nozzle of the inhaler and elsewhere.When the same drug containing agglomerates were stabilized by exposureto humidity as discussed herein, the resulting agglomerates were hard,free-flowing and easily handled. The internal bond strength wasincreased, allowing for proper handling characteristics. Yet theagglomerates remained soft enough to yield an acceptable fine particlefraction.

The present invention results in a higher degree of dosing uniformity.As shown in Table 1, agglomerates produced in accordance with thepresent invention were loaded into 10 inhalers as described in theaforementioned WO 94/14492. The inhalers were set to deliver 100 μg ofmometasone furoate per inhalation. Mometasone furoate was provided in aratio of 1:5.8 to anhydrous lactose (680 μg total agglomerate) and wereproduced as described in Example 1.

TABLE 1 Dose Uniformity Over the Labeled Number Of Inhalations (EmittedDose) Initial Unit Dose Middle Unit Dose Final Unit Dose Inhalation 1Inhalation 60 Inhalation 120 Inhaler Number (μg) (μg) (μg) 1 91 101 98 291 96 93 3 99 89 90 4 88 100 100 5 105 100 96 6 95 95 96 7 106 106 96 892 96 89 9 109 100 93 10  90 95 100 Average 97 98 95 % CV** 7.9 4.7 4.0*Ideal dose is 100 μg **Percent Coefficient of VariationThe emitted dose was determined using a Dosage Unit Sampling Apparatusfor Dry Powder Inhalers similar to that described in PharmaceuticalForum, Vol 20, No. 3, (1994) pp. 7494. The emitted dose was collectedusing a separators funnel attached at one end to a sintered glass filterat an air flow rate of 60 L/minute for a total of 4 seconds. The drugwas then dissolved in a solvent and analyzed using HPLC as is known inthe art. It is clearly evident from a review of Table 1 that from afirst inhalation dose, through the 120th, there is great consistency. Inaddition, the consistency from inhaler to inhaler is significantlyhigher than one would normally expect. Perhaps most importantly, theaverage over all 120 doses for 10 inhalers shows great consistency.These numbers also indicate that very little material is lost duringdosing. Thus, hang-up and dosing problems resulting from filling thedosing hole are minimized.

The fine particle fraction (as a percentage of the total dose) resultingfrom these emitted doses was also tested (Table 2). The fine particlefraction (≦6.8 μm) was determined at a 60 L/minute flow rate using amulti-stage (5-stage) liquid impinger manufactured by Copley Industries(Nottingham) LTD.

TABLE 2 Inhaler Initial Unit Dose Middle Unit Dose Final Unit DoseNumber Inhalation 1 Inhalation 60 Inhalation 120 1 28 24 25 2 19 21 22 327 25 22 Average 24 23 23

The measured fine particle fraction from each inhaler was greater than10% and, in addition, was greatly uniform from the first dose throughdose 120.

A multi-stage impinger allows one to measure the fraction of certainsized particles in each of its various stages. As illustrated in Table3, there is great uniformity between dose 1 and dose 120 in terms of thecumulative fine particle fraction which are less than the 13 μm, lessthan 6.8 μm, less than 3.1 μm and less then 1.7 μm.

TABLE 3 Particle size Initial Dose* Middle Dose* Final Dose* (μm)Inhalation 1 Inhalation 60 Inhalation 120 <13.0 28 26 26 <6.8 24 23 23<3.1 15 16 16 <1.7 7 8 8 *Average of three determinations.

Finally, as shown in FIGS. 3 and 4, the agglomerates of the presentinvention are very durable. FIG. 4 illustrates the control. In thiscase, it illustrates, graphically, the percent of weight delivered orthe emitted dose, in weight percent, of 10 inhalers over 120 doses each.The inhalers used were the Schering powder inhaler previously identifiedand the doses were 100 μg of mometasone furoate with an anhydrouslactose binder produced as described in to Example 1. FIG. 3 presentsthe same data, for identically configured inhalers, after they had beendropped onto a hard surface from a height of about 122 cm (48 inches). Acomparison of the results memorialized in FIGS. 3 and 4 show that verylittle change is exhibited overall.

The present invention helps ensure an unprecedented degree ofagglomerate uniformity which significantly reduced the variability ofdosing as previously demonstrated. For example, if moisture is addedprior to or during agglomeration, a certain percentage of the solidbinder will begin to convert to a crystalline form. The degree ofcrystal formation can vary greatly from particle to particle. As aresult, the size of the agglomerate and the physical strength of theinterparticulate bonding can vary greatly. In addition, the binder canactually begin to dissolve and this would create bonds which are toostrong. This immediately translates into dose variability duringinhalation and a variability in the terms of the fine particle fractionof drug delivered. The present invention overcomes this problem andefficiently provides uniform agglomerates which are easy to produce,store, handle and administer.

EXAMPLES Example 1

To ensure the quality and uniformity of the product, the environmentalconditions for handling and manufacturing agglomerates in accordancewith the present invention were as follows:

Micronization of mometasone and lactose: 21° C.±2° and 20% RH±5%

Storage of micronized lactose: 21° C.±2° and less than 15% RH

Powder blending and agglomeration: 21° C.±2° and 20% RH±5%

Conversion of powder agglomerates: 25° C.±2° and 50% RH±5%

A Patterson-Kelley V-shape blender installed with a pin intensifier barwas set-up in a clean room with temperature and humidity controlled at21° C. and 20% RH, respectively. Half of the micronized lactoseanhydrous was charged into the V-blender. The micronized mometasonefuroate anhydrous was added next. Then, the balance of the micronizedlactose anhydrous was added.

The V-blender was turned on for 5 minutes at a rotation speed of about24 RPM. Next, the V-blender was rotated for 3 minutes with the pinintensifier bar turned on for the first 1 minute at a pin tip speed ofabout 9 meters/second. The blending protocol was then repeated.

Samples were taken from right, left, and bottom of the V-blender to testthe blend uniformity using a unit-dose sampling thieve.

To agglomerate this mixture, a screen shaker was set up in a clean roomwith temperature and humidity controlled at 21° and 20% RH,respectively, Thirty (30) mesh: screens, pans, and stainless-steelcontainers were washed with 70% alcohol and dried.

Screen/pan combinations were assembled and placed on the shaker. Intoeach 12 inch, 30 mesh screen/pan set, 200 g of the mometasone anhydrouslactose blend in a ratio of 1:5.8 (drug:binder) was added. The powderblend was spread on the screen so that the level of the powder blend waslower than the edge of the sieve frame. The screen/pan was placed on thesieve support plate of the shaker. A stainless-steel sieve cover wasplaced on the top screen.

The timer was then set for 10 minutes and the device was turned on suchthat an eccentric circular shaking with a one inch eccentric orbit at aspeed of about 280 rpm occurred. The screen/pan was also tapped at arate of 150 taps/minute to meter material through the screen. Theprocess was stopped and multiple pans consolidated.

The agglomerates formed were poured onto a 20 mesh screen and the screenwas tapped lightly. The material retained on the 20 mesh screen wasdiscarded.

The agglomerates which passed through the 20 mesh screen were stored inthe suitable containers.

When ready to convert the material, the agglomerates were spread onto astainless-steel tray and exposed in a clean room having a temperatureand humidity controlled at 25° C. and 50% RH, for 24 hours. Theagglomerates were then combined and placed in a suitable container.

The bulk density was determined using a Vanderkamp Tap Density Testerset for one tap. Particle size distribution of the agglomerates wasdetermined using a Malvern 2605L particle size analyzer.

Example 2

Three additional batches were produced in accordance with the processgenerally described in Example 1, The batch size and drug to binderratios are illustrated below in Table 4;

TABLE 4 REPRODUCIBILITY OF MOMETASONE: LACTOSE AGGLOMERATES PARTICLESIZE BULK DISTRIBUTION BULK MMF:LACTOSE DENSITY DIAMETER (μm) UNDER SIZERATIO (g/cm³) 10% 50% 90% mean 0.75 Kg 1:5.8 0.35 420 540 790 580 9.60Kg 1:5.8 0.35 370 510 740 540 9.60 Kg 1:19 0.35 390 540 770 570

As will be readily appreciated, despite varying ratios of binder anddrug, as well as varying batch sizes, a high degree of repeatability wasobserved in terms of bulk density and particle size distribution.Particle size in this context refers to the size of the agglomeraterather than that of the particulate binder and/or drug.

1. A dosage form of a pharmacologically active agent useful foradministration by oral inhalation therapy consisting essentially of:agglomerates of particles of at least one pharmacologically activeagent, and particles of crystalline solid binder, said particles havingan average particle size of 10 μm or less and being provided in a weightratio of between 100:1 to 1:500, wherein said agglomerates have a rangein size from between about 100 and about 1500 μm, and wherein saidagglomerates are characterized by having a crush strength of between 50mg and 5000 mg.
 2. The dosage form of claim 1, wherein said particles ofsaid pharmacologically active agent have an average particle size of 10μm or less.
 3. The dosage form of claim 1, wherein said solid bindercomprises at least one member selected from the group consisting ofpolyhydroxy aldehydes, polyhydroxy ketones, and amino acids.
 4. Thedosage form of claim 1, wherein said solid binder comprises a hydratedor anhydrous saccharide.
 5. The dosage form of claim 1, wherein saidsolid binder comprises anhydrous lactose or a hydrated lactose.
 6. Thedosage form of claim 1, wherein said solid binder comprises anhydrouslactose.
 7. The dosage form of claim 1, wherein said particles of saidsolid binder have an average particle size of 10 μm or less.
 8. Thedosage form of claim 1, wherein said particles of pharmacologicallyactive agent and said solid binder have been mixed to substantialhomogeneity.
 9. The dosage form of claim 1, wherein said particles ofpharmacologically active agent and said solid binder have beenagglomerated in a pan rotated with an eccentric motion.
 10. The dosageform of claim 1, wherein said agglomerates have an average size ofbetween about 300 and about 1000 μm.
 11. The dosage form of claim 1,wherein said agglomerates have a crush strength of between about 50 mgand about 5,000 mg after conversion of said convertible amorphouscontent.
 12. The dosage form of claim 1, wherein said agglomerates havea crush strength of between about 200 mg and about 1,500 mg.
 13. Thedosage form of claim 1, wherein said pharmacologically active agent andsaid solid binder are mixed at a weight ratio of between about 1000:1 to1:1000.
 14. The dosage form of claim 1, wherein said pharmacologicallyactive agent and said solid binder are mixed at a weight ratio ofbetween about 100:1 to 1:500.
 15. The dosage form of claim 1, whereinsaid pharmacologically active agent and said solid binder are mixed at aweight ratio of between about 100:1 to 1:300.
 16. The dosage form ofclaim 1, wherein said pharmacologically active agent and said solidbinder have been agglomerated at a weight ratio of between about 20:1 toabout 1:20.
 17. The dosage form of claim 1, wherein saidpharmacologically active agent and said solid binder have beenagglomerated at a weight ratio of between about 1:3 to about 1:10.